Localization of heme oxygenase-2 immunoreactivity to parasympathetic ganglia of human and guinea-pig airways.
Carbon monoxide (CO), an activator of soluble guanylate cyclase and generated enzymatically by heme oxygenase-2 (HO-2), is thought to function as an intra- and intercellular neurotransmitter in the central and peripheral nervous system. In the present study, the distribution of HO-2 in airway nerves from both humans and guinea pigs was assessed. HO-2 was found in all neuronal perikarya of the intrinsic ganglia of guinea-pig airways and in all ganglion nerve cell bodies localized to the trachea and bronchi of humans. By contrast, nerve fibers innervating the smooth muscle, lamina propria, and epithelium of the airways in both species were devoid of HO-2 immunoreactivity. HO-1, the inducible isoform of heme oxygenase, was not found in airway nerves. The pattern of distribution of HO-2 observed suggests that CO might serve as a modulator of synaptic neurotransmission in the lung and airways rather than as a bona fide neurotransmitter in the smooth muscle, vasculature, or glands. Consistent with this hypothesis, 8-bromo-cyclic guanosine monophosphate (cGMP) (30 microM), a stable, pharmacologically active analog of cGMP, markedly inhibited vagally-mediated cholinergic contractions of the isolated guinea-pig trachea. In subsequent studies, however, neither inhibiting heme oxygenase with zinc protoporphyrin-IX (30 microM) nor inhibiting the soluble isoform of guanylate cyclase with ODQ (3 microM) had measurable effects on vagally-mediated cholinergic contractions of the trachea. These results indicate that CO could play a modulatory role in efferent (parasympathetic) synaptic neurotransmission in the airways, but under normal conditions may not be activated to an appreciable extent during periods of elevated vagal activity.
Canning
B J
BJ
Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland, USA.
Fischer
A
A
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002248:Carbon Monoxide; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005726:Ganglia, Parasympathetic / Q000201:enzymology*; D005730:Ganglionic Blockers / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis* / Q000037:antagonists & inhibitors; D051547:Heme Oxygenase-1; D006801:Humans; D008565:Membrane Proteins; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D010069:Oxadiazoles / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000502:physiology; D012143:Respiratory Physiological Phenomena; D012137:Respiratory System / Q000201:enzymology / Q000294:innervation*; D009435:Synaptic Transmission / Q000502:physiology; D014294:Trimethaphan / Q000494:pharmacology; D014630:Vagus Nerve / Q000502:physiology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D005730:Ganglionic Blockers; D008565:Membrane Proteins; D018727:Muscarinic Antagonists; D010069:Oxadiazoles; D011524:Protoporphyrins; D011810:Quinoxalines; D011950:Receptors, Cholinergic; C017803:zinc protoporphyrin; C016276:8-bromocyclic GMP; D014294:Trimethaphan; D001285:Atropine; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D006162:Guanylate Cyclase; D006152:Cyclic GMP